摘要
背景:生长分化因子11(gdf11)随着年龄的增长而降低,C-C基序趋化因子11(ccl11)的增加与衰老有关。然而,GDF11对血管紧张素II(Ang II)诱导的肥厚性心肌病的影响,以及ANP、BNP和βmhc等卷超载和肥大标志物的表达,以及GDF11与CCL11在肥厚性心肌病中的关系尚不清楚。因此,本研究旨在探讨GDF11对血管紧张素Ⅱ(AngⅡ)诱导的肥厚性心肌病的影响以及对小鼠ANP、BNP和β-MHC的表达,并探讨其可能的分子机制。 方法:构建载体,对病毒进行包装。用血管紧张素II治疗小鼠心肌细胞24h,同时将小鼠心肌细胞分为4组:(1)对照组;(2)血管紧张素II组;(3)血管紧张素II+GDF11组;(4)血管紧张素II+CCL11组。此外,分别用gdf11和ccl11蛋白处理小鼠心肌细胞48小时。在肥厚型心肌病小鼠模型中,用心脏超声测量了收缩和舒张过程中静脉和左室肥厚。用qpcr或western blot检测小鼠心肌细胞和心脏T期ANP、BNP、beta-mhc、ccl11和gdf11的相对表达。采用3’-UTR荧光素酶报告法检测GDF11与CCL11表达的关系。 结果:800纳米Ang-II处理后,小鼠心肌细胞中的anp、bnp和beta-mhc表达显著增加,并用于后续的细胞实验。AngⅡ治疗后,0.2ng/ml gdf11组对小鼠心肌细胞中anp、bnp和beta-mhc表达的抑制作用最强,而50ng/ml ccl11组对其表达的刺激作用最强。与对照组相比,10 ng/ml的GDF11显著降低了小鼠心肌细胞CCL11的表达。接受Ang II治疗的小鼠在收缩期和舒张期均增加了IVS和LVPS的厚度,而GDF11的过度表达显著减弱了这一厚度。在肥厚型心肌病小鼠模型中,gdf11的过度表达减弱了anp、bnp和beta-mhc的表达增加。肥厚型心肌病小鼠血清GDF11相对浓度明显降低,CL11显著升高。GDF11过表达恢复了肥厚型心肌病小鼠模型中GDF11和CC11的浓度。此外,GDF11干扰组CCL11的表达显著增加,而GDF11过表达组在荧光素酶报告试验中CCL11的表达显著降低。 结论:GDF11通过下调小鼠CCL11,减轻了AngⅡ诱导的肥厚性心肌病,减轻了ANP、BNP和β-MHC的表达。
关键词: gdf11,ccl11,肥厚性心肌病,anp,βmhc,心律失常。
Current Molecular Medicine
Title:GDF11 Attenuated ANG II-Induced Hypertrophic Cardiomyopathy and Expression of ANP, BNP and Beta-MHC Through Down- Regulating CCL11 in Mice
Volume: 18 Issue: 10
关键词: gdf11,ccl11,肥厚性心肌病,anp,βmhc,心律失常。
摘要: Background: Growth differentiation factor 11 (GDF11) decreases with age, and increased C-C motif chemokine 11 (CCL11) is involved in aging. However, the effects of GDF11 on Angiotensin II (ANG II)-induced hypertrophic cardiomyopathy and expression of markers for volume overload and hypertrophy such as ANP, BNP and beta-MHC, as well as the relationship between GDF11 and CCL11 in hypertrophic cardiomyopathy are unclear. Therefore, the current study aimed to examine the effects of GDF11 on ANG II-induced hypertrophic cardiomyopathy and expression of ANP, BNP and beta-MHC in mice, and explore possible molecular mechanisms.
Methods: Vectors were constructed and viruses were packaged. Mouse cardiomyocytes were treated with ANG II for 24 h. Meanwhile, mouse cardiomyocytes were divided into 4 groups: (1) control; (2) ANG II; (3) ANG II+GDF11; and (4) ANG II+CCL11. Furthermore, mouse cardiomyocytes were treated with GDF11 and CCL11 proteins for 48 h, respectively. The thickness of IVS and LVPS during systole and diastole were measured by cardiac ultrasound in the mouse model of hypertrophic cardiomyopathy. The relative expression of ANP, BNP, beta-MHC, CCL11 and GDF11 in cardiomyocytes or heart tissue of mice was detected by qPCR or Western blot. 3’- UTR luciferase reporter assay was utilized to examine the relationship between GDF11 and the expression of CCL11.
Results: The expression of ANP, BNP, and beta-MHC in mouse cardiomyocytes was significantly increased after the cells were treated with 800 nM ANG II, which was utilized in the following cell experiments. After ANG II treatment, 0.2 ng/ml GDF11 group displayed the highest inhibition of expression of ANP, BNP and beta-MHC in mouse cardiomyocytes, whereas 50 ng/ml CCL11 group displayed the highest stimulation of the expression. GDF11 at 10 ng/ml significantly decreased the expression of CCL11 in mouse cardiomyocytes as compared to the control group. Mice treated with ANG II had increased thickness of IVS and LVPS during both systole and diastole, which was significantly attenuated by GDF11 overexpression. GDF11 overexpression attenuated the increase in expression of ANP, BNP and beta-MHC in the mice model of hypertrophic cardiomyopathy. The relative serum concentration of GDF11 was markedly decreased, and CCL11 was dramatically increased in mice with hypertrophic cardiomyopathy. GDF11 overexpression restored the serum concentration of GDF11 and CCL11 in the mice model of hypertrophic cardiomyopathy. In addition, GDF11 interference group had markedly increased expression of CCL11, whereas GDF11 overexpression group had significantly decreased expression of CCL11 in luciferase reporter assay.
Conclusions: GDF11 attenuated ANG II-induced hypertrophic cardiomyopathy and expression of ANP, BNP and beta-MHC through down-regulating CCL11 in mice.
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GDF11 Attenuated ANG II-Induced Hypertrophic Cardiomyopathy and Expression of ANP, BNP and Beta-MHC Through Down- Regulating CCL11 in Mice, Current Molecular Medicine 2018; 18 (10) . https://dx.doi.org/10.2174/1566524019666190204112753
DOI https://dx.doi.org/10.2174/1566524019666190204112753 |
Print ISSN 1566-5240 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5666 |
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